Optimization of an integrin enhancing molecule for the treatment of Duchenne muscular dystrophy

Abstract Duchenne Muscular Dystrophy (DMD) is a fatal muscle disease with an incidence of 1 in 5000 males. DMD results from mutations in the gene encoding dystrophin, a 427 kDa scaffolding protein responsible for providing a mechanical link between the muscle fiber actin cytoskeleton and laminin in the extracellular matrix. The α7β1 integrin is a transmembrane linkage system in skeletal and cardiac muscle that also links laminin to the actin cytoskeleton. Studies have demonstrated that transgenic and virally mediated overexpression of the α7 integrin alleviates disease progression and improves survival of mouse models of DMD. Loss of the α7 integrin in dystrophin-deficient mdx mice results in severe muscle disease. Together these studies demonstrate that the α7β1 integrin can serve as a surrogate for the loss of dystrophin and is a target for drug-based therapies. The Burkin lab has previously shown treatments with compounds that increase the α7 integrin in dystrophic muscle lead to enhanced muscle regeneration, improved skeletal muscle strength and decreased myofiber damage. In the Phase 2A STTR, Strykagen has shown that treatments with our lead Stryka969 small molecule are safe, on- target, and have beneficial effects for both dystrophic mouse skeletal and cardiac muscle. In this Phase 2B SBIR proposal, we propose to complete IND-enabling Stryka969 tier 2 ADME, organ toxicity, and metabolite profiling studies. We will also assess the serum pharmacokinetics of Stryka969 in both canine and non-human primates. Lastly, we will perform an efficacy study in the large animal GRMD dog model, considered the gold standard animal model for DMD. These studies will scale the therapeutic treatment using Stryka969 in a large animal preclinical model that more closely recapitulates DMD patient skeletal and cardiac disease. Results from this study will move Stryka969, as a first in class α7β1 integrin enhancing molecules, towards IND and clinical trials for patients with DMD.